ME/CFS and Long COVID Demonstrate Similar Bioenergetic Impairment and Recovery Failure on Two-Day Cardiopulmonary Exercise Testing

Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is common in people with Long COVID, including post-exertional malaise (PEM). The overlapping observation of PEM in pre- and post-COVID forms of ME/CFS suggests the potential for shared bioenergetic impairments, but this has not yet been demonstrated. Two cardiopulmonary exercise tests (CPET) administered 24 h apart can elucidate the metabolic underpinnings of each disease. This retrospective study examined physiological responses during two-day CPET in people with ME/CFS (63 females/21 males), Long COVID (52 females/27 males), and matched non-disabled control participants (51 females/20 males). Data were analyzed within sexes using repeated measures analysis of variance. All participants met maximal effort criteria. There were significant reductions in oxygen consumption (V̇ O₂) and workload at the ventilatory anaerobic threshold (VAT) in both patient groups compared to non-disabled controls, with larger effect sizes at VAT than at peak exertion. Performance decrements were observed in both sexes. Females exhibited more pronounced abnormalities and significant group by test effects. No significant differences were observed between patient groups. Severe disability based on impaired V̇ O₂ was prevalent in both patient groups. Hemodynamic and ventilatory measures were within normal ranges. ME/CFS and Long COVID both involve a functionally significant bioenergetic failure complicated by inadequate post-exertional recovery, which is similar between the conditions and unexplained by hemodynamic and ventilatory changes. Findings support the utility of two-day CPET as an objective measure functional impairment in ME/CFS. Future studies may integrate mechanistic biomarkers with two-day CPET as trial endpoints and to establish likely responses to treatments for PEM.